SINGAPORE—A global research team led by scientists from Singapore and the U.S. has discovered new evidence of an underlying link between degeneration of the eye and brain. They found that genetic variation at a beta-amyloid gene was significantly associated with increased risk of primary open angle glaucoma (POAG). The study was published yesterday in the Journal of the American Medical Association (JAMA).

The beta-amyloid gene association was identified specifically in people with African ancestry. The high-risk variant was common in African populations (around 20 percent), but essentially absent in all other ancestral groups.

“Glaucoma in Africans is severe, striking early and often leading to blindness,” said Dr. Michael A. Hauser, professor of Medicine and Ophthalmology at the Duke University Medical Center. “Our data shows that glaucoma in Africa has a different genetic structure than glaucoma in Europe or Asia. We hope that our work to better understand African glaucoma will help preserve sight in people of African ancestry around the world.”

According to the article’s abstract, “A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects.”

The research findings confirmed the suspicion that glaucoma may not only be an eye disease, but also linked to brain degeneration. Two lines of evidence were established: genetic variation at a beta-amyloid gene family was observed to be significantly associated with POAG risk, and beta-amyloid deposits were also significantly increased in eye and brain tissues of patients with POAG compared to unaffected individuals. Beta-amyloid is one of the best-known causes for nerve cell death in Alzheimer’s disease and dementia.

“Family members of patients with glaucoma have a genetically higher chance of contracting glaucoma. The earlier the age of onset and the more severe the disease, then the higher the likelihood that the patient and family members are genetically predisposed and should therefore explore potential interventions,” explained Dr. Khor Chiea Chuen, Group Leader at Genome Institute of Singapore (GIS).

“This was a huge multi-national effort with much of the research conducted in Singapore. The findings are very interesting as it shows the diverse genetic make-up of glaucoma in different populations from around the world,” continued Prof. Aung Tin, executive director of SERI and professor at Yong Loo Lin School of Medicine, National University of Singapore. “We need to better understand the role of this gene in the glaucoma disease process, so that we can develop new therapies in the future.”

“This important finding for POAG research was only possible because of the collegiality and collaboration of nearly all major groups with POAG subjects of African descent,” added Prof. Neil Risch, director, Center for Human Genetics, UCSF and Lamond Family Foundation Distinguished Professor in Human Genetics. “As is typical in studies of this type, very large samples are required, and this study represents by far the largest collection of POAG subjects of African descent in the world, derived from many countries and continents.”

Another recently conducted study on a large multi-ethnic sample, the Genetic Epidemiology Research On Adult Health & Aging cohort in the U.S., confirmed the highest prevalence of POAG in African ancestry individuals (16.1 percent) compared to East Asians (9.9 percent) and Europeans (7.4 percent).

“These findings are crucial in efforts to pinpoint why certain groups of people suffer from severe glaucoma, particularly early on in life. It also suggests that degeneration of the eye and brain could be mechanistically related. This research may lead to solutions to slow down disease onset and lower disease severity,” noted Prof. Patrick Tan, executive director of GIS.

African populations hold a treasure trove of unexplored genomic information; they have been understudied and under-represented in genomic research, despite our understanding that modern humans originated in Africa approximately 200,000 years ago, and 99 percent of the human evolutionary experience has been in Africa. The team studied POAG in Africans and African-descent populations to obtain biological and clinical insights which were unavailable in European and Asian studies.

“The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry,” the abstract continues. “If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.”

The JAMA study findings are expected to change the way researchers perceive glaucoma. Scientists have also begun to look for neuroprotective mechanisms, which could illuminate new ways to treat the disease.